A fundamental goal in the field of neuroscience is to learn how the brain processes sensory information. Understanding how neurons represent sensory stimuli under normal conditions provides the ability to identify compromised components in situations of pathology and develop specific, targeted strategies to treat them. The rodent olfactory system presents many unique advantages to probe sensory coding schemes, including that it is anatomically compact and is fully amenable to all current genetic tools. The field has made great progress since the discovery that families of olfactory receptor genes define many discrete channels of information providing the input to the olfactory bulb through glomeruli1. Still, there is no cohesive theory for how neural codes in the olfactory system build representations of odor features. This proposal approaches the question by proposing a model to link the representations on the input and output levels of the olfactory bulb and testing its predictions experimentally. Specifically, the project seeks to explain the source o the temporal structure observed in responses of the population of mitral and tufted cells (MTCs), each of which receives input from a single glomerulus, and which form the output of the bulb. Our core hypothesis is that the sequence in which an odor activates glomeruli directly influences the sign and timing of responses in the connected MTCs. Aim 1 tests the basic prediction of the model: that the earlier glomeruli in the spatiotemporal sequence activated by an odor will evoke mainly early, excitatory responses in the connected MTCs, while cells receiving input from later glomeruli will show a heterogeneous set of responses. Aim 2 will determine if this coding scheme holds over a range of concentrations, as the underlying mechanism in the model predicts. Aim 3 causally probes whether earlier activation of a glomerulus within the population decreases heterogeneity of responses of its MTCs. The proposed coding scheme has the potential to convey information about the identity of an odor in a way that is tolerant to changes in concentration. These ideas will be tested using recent technological advances in optogenetics and electrophysiology that allow the researchers to target and record odor activity from MTCs that are functionally connected to a specific glomerular channel. The proposed experiments will form the basis of the Primary Investigator's graduate dissertation work and will be carried out over the next 3 years. The Sponsor will provide guidance throughout the process, and particularly with the computational aspects and analyses. The work will be presented at scientific meetings and will be published and made available to the public when completed.